Onset-hastened/enhanced analgesia

ABSTRACT

Onset-hastened and enhanced analgesic response is elicited in a mammalian organism in need of such treatment, i.e., a mammal suffering pain, by administering thereto a unit dosage onset-hastening/enhancing analgesically effective amount of the S(+) ibuprofen enantiomer, said enantiomer being substantially free of its R(-) ibuprofen antipode.

BACKGROUND OF THE INVENTION

1. Field of the Invention:

The present invention relates to the use of S(+) ibuprofen to elicit anonset-hastened and enhanced analgesic response in mammalian organisms inneed of such treatment, and to certain pharmaceutical compositionscomprising unit dosage effective amounts of S(+) ibuprofen.

2. Description of the Prior Art:

Ibuprofen, or (±) 2-(p-isobutylphenyl)propionic acid, has the structuralformula ##STR1##

The compound is well-known as a nonsteroidal antiinflammatory drughaving analgesic and antipyretic activity. Ibuprofen is currentlymarketed by prescription in the United States generically, as well asunder tradenames such as Motrin®, which is available in 400, 600 and 800mg tablets for oral administration. Ibuprofen has recently also becomeavailable in this country in non-prescription strength (200 mg) under avariety of tradenames, including Advil® and Nuprin®, as well as ingeneric form. For the treatment of mild to moderate pain, 400 mg every 4to 6 hours, not to exceed 3200 mg daily, is generally recommended forMotrin®. The lower dose over-the-counter products are generallyrecommended for minor aches and pains, to be used orally at the 200 to400 mg level, every 4 to 6 hours, not to exceed 1200 mg daily unlessdirected by a physician. See also Physician's Desk Reference, 40thedition, 1986, publisher Edward R. Barnhart, Medical Economics Company,Inc., Oradell, N.J. 07649, pp. 1854-1855 and 1897.

As is apparent from its chemical nomenclature, ibuprofen is a racemicmixture. It is only the racemic mixture which has in fact ever beenmarketed. There have, however, been some studies of the individual S(+)and R(-) isomers reported in the literature. These generally reflectthat the R(-) isomer is rapidly converted to the S(+) enantiomer, whichis the active form of ibuprofen.

Adams et al, Curr. Med. Res. Opin., 3, 552 (1975) and J Pharm.Pharmacol., 28, 256-257 (1976), reported that in vivo anti-inflammatoryand analgesic tests in guinea pigs, rats and mice comparing the dextro(+), levo (-) and racemic mixture forms of ibuprofen showed the threeforms to be very similar in potency. (The in vivo tests were conductedin an acetylcholine-induced writhing test in the mouse, in a painthreshold technique test using the yeast-inflamed paw of the rat andusing ultraviolet erythema in the guinea pig.) In vitro, however, it wasfound that nearly all of the activity resided in the dextrorotatoryform. The authors concluded that the in vitro results suggested that thedextro (+) form was the active one, but that in vivo the levo form wasconverted to the dextro form so that there was little difference inpharmacological activity. This was also seen to be an explanation forearlier observations [Adams et al, J. Pharm. Sci., 56, 1686 (1967) andMills et al, Xenobiotica, 3, 589-598 (1973)] that ibuprofen's urinarymetabolites in man were found to be dextrorotatory. Thus, it has beenrecognized for over a decade that the S(+) isomer is the active form.

Wechter et al, Biochem. Biophys. Res. Commun., 61, 833-837 (1974)reported the results of tests in healthy human subjects designed todetermine the stereochemistry involved in ibuprofen's metabolism and therelative stereochemical relationships between ibuprofen's opticalisomers and its metabolic products. They found there was a facileepimerization of ibuprofen's R(-) isomer to the S(+) isomer andconcluded that this accounted for the essential bioequivalence of theR(-) and S(+) isomers.

Related observations were reported by Vangiessen et al, J. Pharm. Sci.,Vol 64, No. 5, 798-801 (May 1975), who found that after oraladministration of the racemic mixture to human volunteers, thepredominant enantiomer in the peripheral circulation and excreted in theurine was of the d-configuration. Vangiessen et al estimated that theplasma drug disappearance half-lives for the d- and l-isomer were 3.34and 2.01 hours, respectively. The concentration ratio of d to lincreased progressively with time from 1.17 at one hour to 2.65 at eighthours; however, these estimates are compromised by the small sample size(n=3), the fact that normal subjects were used, and the extremely largestandard deviations from the mean at the earliest (one-hour) post-dosingtime point. Interpretation of the results of this study is furthercompromised because S(+) was not administered alone so that nocomparisons with the racemate are possible.

Subsequently, Kaiser et al., J. Pharm. Sci., Vol. 65, No. 2, 269-273(February 1976) reported on characterization of enantiomericcompositions of ibuprofen's major urinary metabolites after oraladministration of the racemic mixture and the individual S(+) and R(-)isomers to healthy human subjects. It was found that only the R(-)enantiomer of the intact drug was inverted to its optical antipode,S(+).

Hutt et al, J. Pharm. Pharmacol., 35, 693-704 (1983), reviewed theearlier work on the metabolic chiral inversion of 2-arylpropionic acids,including ibuprofen, which they indicate was the first substituted2-arylpropionic acid conclusively shown to undergo the inversion as wellas the most studied member of the group. The authors again noted thatAdams et al (1976) found no significant difference in in vivo activityamong the R(-) and S(+) isomers and the racemic mixture in threedifferent animal models, but very large differences in vitro between theR(-) and S(+) isomers, ascribing this discrepancy to the virtuallyquantitative conversion of the R(-) to the active S(+) isomer in vivo.Hutt et al indicated similar properties for fenoprofen. The enantiomersof fenoprofen were reported to be of equal potency in animal testsystems.

In the same paper, Hutt et al reported that, in contrast, for severalother 2-arylpropionic acids, the inactive R(-) isomer was not convertedin vivotto the active S(+) isomer as readily as ibuprofen andfenoprofnn, although the conversion seemed to occur to some extent overtime. Naproxen, they noted, has been the only compound marketed as theS(+) enantiomer to date. And in the case of indoprofen, the R(-)enantiomer was found to be about 20 times less pharmacologically activein rats and mice in vivo than the S(+) isomer. Hutt et al concluded:

It is likely that benefits will be obtained from the use of theS(+)-enantiomer of 2-arylpropionates as drugs as opposed to theracemates. This is only found at present in the case of naproxen. Incases of rapid inversion, the inactive R(-) isomer serves merely as aprodrug for the active S(+)-antipode. Where inversion is slow, the R(-)enantiomer is an unnecessary impurity in the active S(+) form. Use ofthe S(+)-enantiomer would permit reduction of the dose given, removevariability in rate and extent of inversion as a source of variabilityin therapeutic response and would reduce any toxicity arising fromnon-stereospecific mechanisms.

Thus, in cases of rapid inversion, such as ibuprofen and fenoprofen,where substantially equivalent in vivo responses have been reported forthe individual enantiomers and the racemic drug, Hutt et al suggestedthat no benefits would be obtained from the use of the S(+) isomerbecause the inactive R(-) isomer merely acts as a prodrug for the activeS(+) form. Contrariwise, in cases where chiral inversion is slow, e.g.naproxen and indoprofen, the use of the S(+) enantiomer is desirable forseveral reasons enumerated by Hutt et al. Indeed, naproxen has beenreported to be marketed as the d-isomer for one of the reasons given byHutt et al, i.e. to reduce side effects (Allison et al, "Naproxen,"Chapter 9 in Anti-inflammatory and Anti-Rheumatic Drugs, eds. Rainsfordand Path, CRC Press Inc., Boca Raton, Fla., 1985, p. 172).

Another general report on earlier work has been provided by Hutt et alin Clinical Pharmacokinetics, 9, 371-373 (1984). In this article on theimportance of stereochemical considerations in the clinicalpharmacokinetics of 2-arylpropionic acids, the authors tabulatedrelative potencies of the enantiomers of a number of 2-arylpropionicacids in vivo and in vitro. The in vitro results showed the S or (+)isomer in each case to be the active species. In vivo, however, theresults were not consistent across the entire class. Thus, the resultsfor naproxen and indoprofen demonstrate the S or (+) isomer to be muchmore active in vivo, indicating a relatively slow inversion of theinactive R or (-y) isomer to the active S or (+) isomer; the results forfenoprofen and ibuprofen, on the other hand, demonstrate the inactive Ror (-) and the active S or (+) isomers to be approximately equallyeffective in vivo, indicating a rapid inversion of R or (-) isomer to Sor (+) isomer.

The medicinal chemistry of 2-arylpropionic acids and other NSAIDs(non-steroidal anti-inflammatory drugs) has been reviewed by Shen inAngewandte Chemie International Edition, Vol. 11, No. 6, 460-472 (1972)and in "Nonsteroidal AntiInflammatory Agents," Chapter 62 in Burger'sMedicinal Chemistry, 4th edition, part III, Wiley Interscience, New York(1981), pp. 1205-1271. In the latter publication, Shen notes thatibuprofen is used as a racemic mixture because the two optical isomersare equally potent in the UV erythema assay, a commonly usedanti-inflammatory model.

Lee et al, Br. J. Clin. Pharmac. 19, 669-674 (1985), administeredracemic ibuprofen and each of the enantiomers separately to four healthyhuman males, then studied stereoselective disposition. They estimatedthat about 63% of the dose of R(-) was inverted to the S(+) enantiomerover a 14 hour period. Lee et al noted that the kinetics of the S(+) andR(-) enantiomers were changed when the respective optical antipode wasconcurrently administered. The authors speculated that this alterationreflected an interaction between the R(-) and S(+) forms at the bindingsites for plasma protein. An ibuprofen plasma level time profile for asingle subject is shown graphically in the paper and might suggest thatthere was minimal conversion in the early hours of the study, but theauthors did not appear to attach any significance to this. Lee et alindicated that the half-life of S(+) after administering the racematewas 2.5 hours, whereas the half-life of S(+) after administering S(+)was 1.7 hours. The authors recognized the limitations of their work, forreasons including the small number of subjects studied, and anassumption that the clearance of S(+) is unchanged betweenadministrations of R(-) and S(+). They also cautioned that it is quitelikely that the fraction of R(-) that is inverted to S(+) varies fromindividual to individual.

Cox et al, J. Pharmacol. Exp. Ther., Vol. 232, No. 3, 636-643 (1985),carried out liver perfusion experiments to study the role of the liverin the clearance of the stereoisomers of ibuprofen in normal and diseasestates. Experiments were conducted with normal and fatty rat liver.Results showed that when liver is fatty, clearance of the R(-) isomer isaffected and preferential S(+) hepatic distribution is eliminated.However, the effects were predicted to have only minimal impact on totalibuprofen plasma levels following racemic ibuprofen dosing.

Cox et al, abstract in Amer. Soc. Clin. Pharmacol. Ther., February 1987,200 (abstract PIIL-7) described a three way crossover study in whichsingle doses of ibuprofen solution were given orally to twelve healthyhuman males. The doses given were 800 mg of racemic ibuprofen, 400 mg ofR(-) ibuprofen and 400 mg of S(+) ibuprofen. Based onarea-under-the-curve measures, significant chiral inversion was observedfor R(-) but not for S(+). Elimination of S(+) was inhibited as plasmaconcentration of R:S increased. The extent of R(-) inversion, based onurinary data, was the same for the racemate and the R(-) isomer, with amean of 0.66. Again, the authors gave no information as to what occurredin the first two hours. The statement on reduced clearance of S(+) inthe racemate is consistent with the finding of increased length of S(+)half-life after administering the racemate found by Lee et al.

Laska et al, Clin. Pharmacol. Ther., Vol. 40, No. 1, 1-7 (July 1986),reported that administration of racemic ibuprofen to patients withmoderate to severe pain subsequent to third molar extraction gavecorrelations between pain intensity ratings and serum levels ofibuprofen. Correlations were found between contemporaneous serum levelsand measures of pain intensity improvement, supporting the propositionthat increased ibuprofen serum levels lead to increased analgesia,particularly in the first few hours after dosing. However, the authorsdid not correlate analgesia with either isomer of ibuprofen; thepossibility of critical differences between free and bound ibuprofen andbetween the S(+) and R(-) isomers was not addressed.

In summary, the current state of the art recognizes that, in mammals,the S(+) form is the active enantiomer of ibuprofen. The art furtherrecognizes that there is a significant, relatively rapid conversion invivo of R(-) to S(+), with little if any conversion of S(+) to R(-).Furthermore, in the only animal experiments on efficacy reported in theliterature, it was noted that there were no significant differences inpotency between the racemate and the enantiomers. This is attributed tothe rapidity of the chiral inversion. This would suggest there would beno benefit to be derived from the use of S(+) ibuprofen for analgesia.Indeed, use of S(+) alone would appear to reduce the half-life of theactive drug. The prior art, moreover, is conspicuously silent in respectto any onset-hastened/enhanced alleviation of mammalian pain utilizingwhatever form of the ibuprofen drug species.

SUMMARY OF THE INVENTION

Surprisingly, the present inventors now find that S(+) ibuprofen can beadvantageously administered to mammals suffering from pain, especiallyhumans, to not only elicit a more potent analgesic response but also toevoke such response more rapidly than possible by administration of thesame dose of ibuprofen in its racemic form.

This is particularly surprising in light of the art's failures toattribute any significative difference in activity in vivo for S(+)ibuprofen versus the racemic mixture, a failure which the presentinventors brand as resulting from the lack of telling observations ofthe pain level or amount of relief at meaningful time pointssufficiently soon after dosing in an appropriate analgesic model.

In one aspect, the present invention thus provides a method of hasteningthe onset of analgesia in a mammal, said method comprising administeringto a mammal in need of such treatment an effective onset-hasteninganalgesic amount of S(+) ibuprofen substantially free of R(-) ibuprofen.

In another aspect, the present invention provides a method of elicitingan enhanced analgesic response in a mammal, particularly shortly afterdosing, said method comprising administering to a mammal in need of suchtreatment an effective analgesia enhancing amount of S(+) ibuprofensubstantially free of R(-) ibuprofen.

In yet another aspect, the present invention provides a pharmaceuticalcomposition of matter for use in eliciting an onset hastened andenhanced analgesic response in mammals, especially humans, saidcomposition comprising an effective analgesic unit dosage amount of S(+)ibuprofen substantially free of R(-) ibuprofen. Typically, S(+)ibuprofen is associated with a nontoxic pharmaceutically acceptableinert carrier or diluent therefor.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

The term "ibuprofen" or "racemic ibuprofen" as used herein is intendedto encompass not only (±) 2-(p-isobutylphenyl)propionic acid itself butalso any pharmaceutically acceptable salt thereof, e.g. ibuprofenaluminum.

The term "S(+) ibuprofen" as used herein is intended to encompass notonly the dextrorotatory or S(+) isomer of 2-(p-isobutylphenyl)propionicacid but also any pharmaceutically acceptable, analgesically effectivesalt thereof. The expression "substantially free of R(-) ibuprofen" asused in conjunction with the term "S(+) ibuprofen" means that the S(+)ibuprofen is sufficiently free of R(-) ibuprofen [which is thelevorotatory form or R(-) isomer of 2-(p-isobutylphenyl)propionic acidor salt thereof]to exert the desired onset-hastened and enhancedanalgesic effect. Practically speaking, this means that the activeingredient should contain at least 90% by weight S(+) ibuprofen and 10%or less by weight R(-) ibuprofen. Preferably, the weight ratio of S(+)ibuprofen to R(-) ibuprofen is greater than 20:1, more preferablygreater than 97:3. Most preferably the S(+) ibuprofen is 99 or more % byweight free of R(-) ibuprofen, i.e., the weight ratio of S to R isapproximately equal to or greater than 99:1.

Where specific amounts of S(+) ibuprofen are set forth below, it shouldbe understood that, unless otherwise specified, the amounts are given inmg of the acid, not of a salt. Moreover, unless otherwise specified, forsimplicity's sake the amounts given represent total ibuprofen content,most of which is in the S(+) form. For example, "400 mg S(+) ibuprofen"means 400 mg total ibuprofen at least 90% of which is in the S(+) form,preferably at least 95%, more preferably at least 97% and mostpreferably 99% or more.

S(+) ibuprofen, in accord with the present invention, produces thefollowing unexpected results:

(1) the analgesic effect of ibuprofen on the mammal is brought on morequickly than by use of the same dose of racemic ibuprofen; and

(2) a greater analgesic response is elicited in the early hours than iselicited by the same dose of racemic ibuprofen.

These unexpected results can be achieved in the treatment of painresponsive to an NSAID (non-steroidal antiinflammatory drug) andspecifically pain associated with inflammation. This includes postpartumand postoperative pain, dental pain, headache pain, dysmenorrhea, painof musculoskeletal origin and pain and discomfort associated withrespiratory infections such as colds and flu.

For patients suffering from such pain, who require treatment at aparticular dose of racemic ibuprofen, the time from administration ofmedication to the onset of effective relief is clearly of paramountimportance. The present inventors' discovery that S(+) ibuprofen, whenused in place of racemic ibuprofen at the same dose, substantiallyshortens the onset time (i.e., substantially hastens the onset) ofanalgesia is therefore very significant. It is likewise quiteunexpected. Moreover, in patients suffering from inflammatory ordegenerative joint disease, e.g. rheumatoid arthritis, osteoarthritis,gout or acute musculo-skeletal disease, the substantial shortening ofanalgesic onset is extremely important; pain is an important componentof these disease states and more rapid relief from pain is ofsubstantial psychological benefit. The S(+) ibuprofen will, of course,over time provide relief from other aspects of inflammatory disease aswell, including, e.g. morning stiffness.

In a group responsive to a given dose of the racemate, it is believedthat onset time for analgesia can be reached, on the average, aboutone-third sooner when S(+) ibuprofen is used rather than when racemicibuprofen is administered, depending on the dose level and the severityof the pain, but particularly at the low end (100-400 mg) of theanalgesic dosage range and for patients with moderate pain.

Insofar as concerns enhanced analgesia, more pronounced analgesia isobtained when S(+) ibuprofen is used at the same dose level as racemicibuprofen, especially during the first few hours.

The precise amount of S(+) ibuprofen for use in accord with the presentinvention will vary depending, for example, on the size and kind of themammal and the condition for which the drug is administered. For use inhumans, the analgesically effective amount of S(+) ibuprofen willtypically be from about 100 to 600 mg, although greater amounts (e.g.1000 mg) may be employed if needed for pain relief and if tolerated bythe patient. The daily dose in humans preferably will not exceed 3200 mgS(+) ibuprofen, although greater amounts could be employed if toleratedby the patient. Preferred unit dosage compositions for use in thetreatment of mild to moderate pain having an inflammatory componentcontain 50, 100, 200, 400, 600 or 800 mg S(+) ibuprofen.

While the compositions for use in the invention are preferably for oraluse, they may also be formulated for and administered by other routeswhich are known for administering non-narcotic analgesics/nonsteroidalanti-inflammatory drugs, e.g. as suppositories or parenteral solutions,or as topical formulations such as ointments, gels, creams, lotions,solutions, impregnated bandages or other topical delivery devices, andso forth. Also, it should be noted that the preferred human dosagelevels indicated above are for use in adults; pediatric compositionswould contain proportionately less of the active ingredient.

The compositions for use herein are very conveniently administered tomammals by any route of administration suitable for racemic ibuprofen,e.g. oral, rectal, topical or parenteral. Preferably S(+) ibuprofen isformulated with any suitable nontoxic pharmaceutically acceptable inertcarrier material. Such carrier materials are well known to those skilledin the art of pharmaceutical formulations. For those not skilled in theart, reference is made to the text entitled Remington's PharmaceuticalSciences, 17th edition, 1985, ed. Alfonso R. Gennaro, Mack PublishingCompany, Easton, Pa. 18042. In a typical preparation for oraladministration, e.g. tablet, capsule or caplet, S(+) ibuprofen in aneffective analgesic amount and substantially free of R(-) ibuprofen, iscombined with any oral nontoxic pharmaceutically acceptable inertcarrier such as lactose, starch (pharmaceutical grade), dicalciumphosphate, calcium sulfate, kaolin, mannitol and powdered sugar.Additionally, when required, suitable binders, lubricants,disintegrating agents and coloring agents can also be included. Typicalbinders include starch, gelatin, sugars such as sucrose, molasses andlactose, natural and synthetic gums such as acacia, sodium alginate,extract of Irish moss, carboxymethylcellulose, methylcellulose,polyvinylpyrrolidone, polyethylene glycol, ethylcellulose and waxes.Typical lubricants for use in these dosage forms can include, withoutlimitation, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine and polyethylene glycol. Suitable disintegrators caninclude, without limitation, starch, methylcellulose, agar, bentonite,cellulose, wood products, alginic acid, guar gum, citrus pulp,carboxymethylcellulose and sodium lauryl sulfate. If desired, aconventional pharmaceutically acceptable dye can be incorporated intothe dosage unit form, i.e., any of the standard FD&C dyes. Sweeteningand flavoring agents and preservatives can also be included,particularly when a liquid dosage form is formulated, e.g. an elixir,suspension or syrup. Also, when the dosage form is a capsule, it maycontain, in addition to materials of the above type, a liquid carriersuch as a fatty oil. Various other materials may be present as coatingsor to otherwise modify the physical form of the dosage unit. Forinstance, tablets, pills or capsules may be coated with shellac and/orsugar. Such compositions should preferably contain at least 0.1% of S(+)ibuprofen; generally, S(+) ibuprofen will be from about 2% to about 60%of the weight of the unit. Typical unit dosage forms for oraladministration will contain about 50 to 1000 mg, preferably 100 to 800mg, most preferably 100 to 600 mg, S(+) ibuprofen, if formulated forimmediate release, as is preferred. If the composition is intended forsustained release, much larger amounts of the active ingredient would ofcourse be incorporated into an individual unit; in such case, at least50, and preferably up to 600 or 800 mg of the total amount of S(+)ibuprofen, should be formulated for immediate release so as to obtainthe desired degree of enhanced analgesia and hastened onset.

A typical tablet for oral administration may contain, in addition to theselected amount of S(+) ibuprofen, the following combination of inactiveingredients/carrier materials: acacia, acetylated monoglycerides,beeswax, calcium sulfate, colloidal silicon dioxide, dimethicone, ironoxide, lecithin, pharmaceutical glaze, povidone, sodium benzoate, sodiumcarboxymethylcellulose, starch, stearic acid, sucrose and titaniumdioxide; or carnauba wax, cornstarch, D&C Yellow No. 10, FD&C Yellow No.6, hydroxypropylmethylcellulose, propylene glycol, silicon dioxide,stearic acid and titanium dioxide.

Moreover, the compositions for use in obtaining enhanced analgesia andhastened onset in accord with the present invention may, in addition tothe selected dose of S(+) ibuprofen, also contain other activeingredients and/or enhancing agents. Thus, for example, S(+) ibuprofenmay be combined with such ingredients and agents as have been describedfor combination with racemic ibuprofen, e.g. caffeine or other xanthinederivative, a narcotic analgesic (with or without caffeine), a skeletalmuscle relaxant, an antihistamine, decongestant, cough suppressantand/or expectorant. See, for example, Sunshine et al U.S. Pat. No.4,420,483, issued Dec. 13, 1983; Sunshine et al U.S. Pat. No. 4,464,376,issued Aug. 7, 1984; Sunshine et al U.S. Pat. No. 4,479,956, issued Oct.30, 1984; Sunshine et al U.S. Pat. No. 4,552,899, issued Nov. 12, 1985;Sunshine et al U.S. Pat. No. 4,558,051, issued Dec. 10, 1985; Sunshineet al U.S. Pat. No. 4,585,783, issued Apr. 29, 1986; and Sunshine et alU.S. Pat. No. 4,619,934, issued Oct. 28, 1986; and Sunshine et alpending U.S. patent application Ser. No. 815,502, filed Jan. 2, 1986.

The enhanced analgesic effect and hastened onset obtained by use of S(+)ibuprofen in comparison with racemic ibuprofen can be evaluated inanimal and human studies such as those described below.

Antiphenylquinone Writhing Test

This test is a standard procedure for detecting and comparing analgesicactivity and generally correlates well with human efficacy.

Mice are first dosed with the medications studied. The medications usedare two dose levels of S(+) ibuprofen and two dose levels of racemicibuprofen. The mice are then challenged with phenyl-p-benzoquinone givenintraperitoneally and observed for the characteristic stretch-writhingsyndrome. Lack of writhing constitutes a positive response. The degreeof analgesic protection can be calculated on the basis of suppression ofwrithing relative to control animals run the same day. Time responsedata are also obtained. Observations are made early enough post-dosingto detect differences in onset. The test is a modification from themethods of Sigmund et al and Blumberg et al (Sigmund, E., Cadmus, R.,and Lu, G., Proc. Soc. Exp. Biol. and Med. 95, 729-731, 1957; Blumberg,H., et al, Proc. Soc. Exp. Biol. and Med. 118, 763-766, 1965).

The Inflamed Rat Paw Test: Pressure Induced Stimuli

The method of Randall-Selitto, modified according to Winter et al, isused to ascertain the escape response threshold resulting from theapplication of increasing pressure to the yeast inflamed left hind paw.Drug treatment is given. The medications studied are two dose levels ofS(+) ibuprofen and two dose levels of racemic ibuprofen. A constantlyincreasing force is applied to the paw and the "flight reaction" isobserved and recorded at several points in time (Randall, L. Q., andSelitto, J. J.: Arch. Int. Pharmacodyn., II, 409-419, 1957; Winter, C.A., and Lars, F.: J. Pharmacol. Exp. Therap. 148, 373-379, 1965).Observations are made early enough post-dosing to detect differences inonset.

To establish the efficacy of the compositions of this invention inhumans, patients with moderate to severe pain requiring an oralanalgesic/anti-inflammatory agent, can be administered S(+) ibuprofen orracemic ibuprofen. Typical pain models include dysmenorrhea,post-operative pain, post-partum pain and dental extraction pain. Eithera crossover design or a completely randomized design can be used. Todetermine analgesic efficacy, an observer interviews the patients as totheir level of pain at subsequent periods of time. Patients are asked tosubjectively estimate the time at which the medication begins to providesignificant relief. Patients may be given a stopwatch to help estimateonset more accurately. Appropriate statistical methods, includingsurvival analysis, can be used to show that the S(+) enantiomer hasshorter onset and is more efficacious (Laska, E., Gormely, M., Sunshine,A., Belleville, J. W., Kantor, T., Forrest, W. H., Siegel, C. andMeisner, M., "A Bioassay Computer Program for Analgesic ClinicalTrials," Clin. Pharmacol. Ther. 8:658, 1967; Cox, D.R., "RegressionModels and Life Tables," Journal Royal Statistical Society, Series B,Volume 34:187-202, 1972).

S(+) ibuprofen for use in the method and compositions of the presentinvention can be prepared by a variety of methods, such as by resolutionof racemic ibuprofen.

Resolution of racemic ibuprofen has been described in the literature.Kaiser et al, J. Pharm. Sci., Vol. 65, No. 2, 269-273 (February 1976)added S(-) α-methylbenzylamine dropwise, with stirring, to a cooledsolution of racemic ibuprofen in ether. The solid S(-)α-methylbenzylamine salt of S(+) ibuprofen thus obtained was removed byfiltration, recrystallized first from isopropanol and then frommethanol, acidified with 3N aqueous sulfuric acid, extracted with etherand washed with water and saline solution. The ether extract wasevaporated to dryness and the resultant white solid was recrystallizedfrom ethanol to give S(+) ibuprofen, m.p. 50°14 52°, [α]_(D) +57°, with95% optical purity as determined by GLC analysis as the S(-)α-methylbenzylamide derivative. Cox et al, J. Pharmacol. Exp. Ther.,Vol. 232, No. 3, 636-643 (March 1985), using Kaiser et al's method, wereable to obtain an S(+) ibuprofen preparation which was 99% S isomer and1% R isomer (w/w).

Generally speaking, the S(+) isomer can be separated from racemicibuprofen by preparing a salt of ibuprofen with an alkaloid or similarresolving agent such as cinchonidine, then separating the products byfractional crystallization from a solvent in which the dextrorotatoryisomer is least soluble. The d-salt can then be acid cleaved to yieldS(+) ibuprofen. Compare, for example, Alvarez U.S. Pat. No. 3,637,767,issued Jan. 25, 1972, which relates to resolution of naproxen andrelated compounds.

When S(+) ibuprofen is to be employed in the form of a pharmaceuticallyacceptable, analgesically active salt thereof, such salt may beconveniently prepared by direct salification of S(+) ibuprofen. CompareArmitage et al U.S. Pat. No. 4,501,727, issued Feb. 26, 1985, whichdescribes the N-methyl-D-glucamine salt of flurbiprofen. Such a salt maynot only be used in oral or rectal compositions, but, if sufficientlysoluble in water, may be useful in the preparation of aqueous solutionsof S(+) ibuprofen for parenteral injection.

From the foregoing description, one of ordinary skill in the art caneasily ascertain the essential characteristics of the instant invention,and without departing from the spirit and scope thereof, can makevarious changes and/or modifications of the invention to adapt it tovarious usages and conditions. As such, these changes and/ormodifications are properly, equitably and intended to be within the fullrange of equivalence of the following claims.

What is claimed is:
 1. The method of eliciting an onset-hastened andenhanced analgesic response in a human mammal suffering from pain and inneed of such treatment, comprising administering to such organism a unitdosage onset-hastening/enhancing analgesically effective amount of theS(+) ibuprofen enantiomer, and said enantiomer being substantially freeof its R(-) ibuprofen antipode.
 2. A method according to claim 1,wherein the weight ratio of S(+) ibuprofen to R(-) ibuprofen is greaterthan 9:1.
 3. A method according to claim 2, wherein the weight ratio ofS(+) ibuprofen to R(-) ibuprofen is greater than 20:1.
 4. A methodaccording to claim 3, wherein the weight ratio of S(+) ibuprofen to R(-)ibuprofen is greater than 97:3.
 5. A method according to claim 4,wherein the weight ratio of S(+) ibuprofen to R(-) ibuprofen isapproximately equal to or greater than 99:1.
 6. A method according toclaim 1, comprising administering to such organism from about 50 toabout 1000 mg S(+) ibuprofen.
 7. A method according to claim 1,comprising administering to such organism from about 100 to about 800 mgS(+) ibuprofen.
 8. A method according to claim 1, comprisingadministering to such organism from about 100 to about 600 mg S(+)ibuprofen.
 9. A method according to claim 2, comprising administering tosuch organism from about 50 to about 1000 mg S(+) ibuprofen.
 10. Amethod according to claim 2, comprising administering to such organismfrom about 100 to about 800 mg S(+) ibuprofen.
 11. A method according toclaim 2, comprising administering to such organism from about 100 toabout 600 mg S(+) ibuprofen.
 12. A method according to claim 3,comprising administering to such organism from about 50 to about 1000 mgS(+) ibuprofen.
 13. A method according to claim 3, comprisingadministering to such organism from about 100 to about 800 mg S(+)ibuprofen.
 14. A method according to claim 3, comprising administeringto such organism from about 100 to about 600 mg S(+) ibuprofen.
 15. Amethod according to claim 4, comprising administering to such organismfrom about 50 to about 1000 mg S(+) ibuprofen.
 16. A method according toclaim 4, comprising administering to such organism from about 100 toabout 800 mg S(+) ibuprofen.
 17. A method according to claim 4,comprising administering to such organism from about 100 to about 600 mgS(+) ibuprofen.
 18. A method according to claim 5, comprisingadministering to such organism from about 50 to about 1000 mg S(+)ibuprofen.
 19. A method according to claim 5, comprising administeringto such organism from about 100 to about 800 mg S(+) ibuprofen.
 20. Amethod according to claim 5, comprising administering to such organismfrom about 100 to about 600 mg S(+) ibuprofen.
 21. A method according toclaim 1, wherein such organism is suffering from postoperative pain. 22.A method according to claim 1, wherein such organism is suffering frompostpartum pain.
 23. A method according to claim 1, wherein suchorganism is suffering from dental pain.
 24. A method according to claim1, wherein such organism is suffering from dysmenorrhea.
 25. A methodaccording to claim 1, wherein such organism is suffering from headachepain.
 26. A method according to claim 1, wherein such organism issuffering from musculoskeletal pain.
 27. A method according to claim 1,wherein such organism is suffering from pain or discomfort associatedwith a respiratory infection.
 28. A method according to claim 1, whereinsuch organism is suffering from pain or discomfort associated with acold or flu.
 29. A method according to claim 1, wherein such organism issuffering from pain associated with inflammatory or degenerative jointdisease.
 30. A method according to claim 1, wherein such organism issuffering from pain associated with rheumatoid arthritis.
 31. A methodaccording to claim 1, wherein such organism is suffering from painassociated with osteoarthritis.
 32. A method according to claim 1,wherein such organism is suffering from pain associated with gout.
 33. Amethod according to claim 1, wherein such organism is suffering frompain associated with morning stiffness.
 34. A method according to claim1, wherein the S(+) ibuprofen is orally administered to such organism.35. A method according to claim 1, wherein the S(+) ibuprofen isrectally administered to such organism.
 36. A method according to claim1, wherein the S(+) enantiomer is topically administered to suchorganism.
 37. A pharmaceutical composition of matter adapted to elicitan onset-hastened and enhanced analgesic response in a mammalianorganism in need of such treatment, said composition comprising asolid-state unit dosage onset-hastening/enhancing analgesicallyeffective amount of the S(+) ibuprofen enantiomer, said enantiomer beingsubstantially free of its R(-) antipode, and a nontoxic pharmaceuticallyacceptable carrier or diluent therefor.
 38. The pharmaceuticalcomposition of matter according to claim 37, adapted for oraladministration.
 39. The pharmaceutical composition of matter accordingto claim 38, formulated as a tablet, caplet, pill or capsule.